Neurophysiological phenotypes are uncoupled from toll-like receptor (TLR)-mediated systemic disease in a model of systemic lupus erythematosus (SLE)

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Presentation Time: 05:00 PM - 05:15 PM
Abstract ID: 5958 - B

Presenting Author:
Cecilia H Stumpf , Research Technician III at Northwestern Univ. Feinberg Sch. of Med.

Abstract:

SLE is a multisystemic autoimmune disease with diverse clinical presentations, including neuropsychiatric symptoms (NPSLE). Prior work implicates uncontrolled MyD88-dependent TLR activation, increased interferon regulatory factor 5 (IRF5) activity and elevated type I interferon (IFN) levels in disease. Immune complexes containing self-nucleic acids can activate endosomal TLRs 7/8/9, which require signaling adaptor MyD88 to modulate downstream gene expression through transcription factor 1) IRF7 to upregulate IFN, which can subsequently act on the IFN-α/β receptor (IFNAR) or 2) IRF5 to upregulate proinflammatory genes. SLE- and NPSLE-prone mice with conditional deletion of signaling mediators MyD88, IRF5 and IFNAR in dendritic cells and tissue resident-macrophages were generated. MyD88 and IRF5 deletion ameliorated systemic disease phenotypes including splenomegaly, lymphadenopathy and glomerulonephritis, but NPSLE-associated phenotypes in the brain, including expansion of total and disease-associated microglia, macrophages and extravascular T cells, persisted. In contrast, IFNAR deletion worsened systemic disease, yet reversed several NPSLE-associated phenotypes. These discoveries suggest an uncoupling of systemic and neurophysiological phenotypes in SLE. Namely, neurophysiological phenotypes manifest independently from the TLR-dependent pathway that drives systemic disease and are instead in part linked to aberrant signaling through IFNAR via mechanisms yet unexplored.